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Dual Hypothermic Oxygenated Perfusion of DCD Liver Grafts in Preventing Biliary Complications After Transplantation (DHOPE-DCD)

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ClinicalTrials.gov Identifier: NCT02584283
Recruitment Status : Recruiting
First Posted : October 22, 2015
Last Update Posted : October 17, 2018
Sponsor:
Collaborators:
Erasmus Medical Center
Leiden University Medical Center
Information provided by (Responsible Party):
Robert J. Porte, University Medical Center Groningen

Brief Summary:

Rationale: Recent publications report good results of controlled donation after circulatory death (DCD) Maastricht category III liver transplantation when strict donor-recipient matching is applied and ischemia times are kept to a minimum. However a major concern remains the high rate of biliary complications after transplantation of DCD livers. Non-anastomotic biliary strictures (NAS) occur in 29% of patients receiving a DCD graft whereas the incidence of NAS in recipients of donation after brain death (DBD) liver grafts is 11%. NAS are associated with higher morbidity and increased cost of liver transplantation. Injury to the biliary epithelium and the peribiliary vascular plexus occurring during donor warm ischemia and static cold storage (SCS) has been identified as a major risk factor for development of NAS. Machine perfusion has been proposed as an alternative strategy for organ preservation, offering the opportunity to improve the quality of the organ by providing oxygen to the graft. Experimental studies have shown that end-ischemic dual hypothermic oxygenated machine perfusion (DHOPE) helps liver grafts to recover from ischemia by restoring mitochondrial function. Moreover, DHOPE has been shown to provide better preservation of peribiliary vascular plexus of the bile ducts, which could be an important step forward in reducing the incidence of NAS after transplantation.

Objective: To study the efficacy of end-ischemic DHOPE in reducing the incidence of NAS within six months after controlled DCD (Maastricht category III) liver transplantation.

Study design: An international, multicenter, prospective, randomized, controlled, interventional, clinical trial with a two parallel arm approach (treatment/control).

Study population: Adult patients (≥18 yrs old) undergoing a liver transplantation with a liver graft procured from a controlled DCD donor (Maastricht category III) with a body weight ≥40 kg.

Intervention: In the intervention group liver grafts will be subjected to two hours of hypothermic, oxygenated perfusion at the end of SCS and before implantation. In the control group donor liver grafts will be preserved in accordance to standard practice by SCS only.

Main study parameters/endpoints: The incidence and severity of symptomatic NAS as diagnosed by an Adjudication committee (who are blinded for the group assignment) by means of magnetic resonance cholangiopancreatography (MRCP).


Condition or disease Intervention/treatment Phase
Liver Failure End Stage Liver Disease Biliary Tract Diseases Procedure: Dual hypothermic oxygenated perfusion Device: Liver Assist® Procedure: Perfusion fluid Drug: Glutathione Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 156 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: A Multicenter Randomized Controlled Trial to Compare the Efficacy of End-ischemic Dual Hypothermic Oxygenated Perfusion With Standard Static Cold Storage of Liver Grafts Donated After Circulatory Death in Preventing Biliary Complications
Study Start Date : October 2015
Estimated Primary Completion Date : April 2019
Estimated Study Completion Date : October 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dual hypothermic oxygenated perfusion
The liver is procured with a segment of supratruncal aorta. The intervention is restricted to the liver graft after arrival in the transplant center and before implantation. The donor liver is subjected to 2 hours of hypothermic oxygenated perfusion via the portal vein and the supratruncal aorta applied by the Liver Assist®. Before perfusion, the liver is flushed via the portal vein with 1 L Belzer machine perfusion solution. The perfusion is pressure controlled and set to a mean of 25 mmHg (arterial) and 5 mm Hg (portal). The perfusion fluid is 4 L Belzer machine perfusion solution with additional 3 mmol/L glutathione. The perfusion fluid is 12°C, when the temperature is set at 10°C. The oxygen flow is set at 0.5 mL/min of 100% oxygen on each of the two membrane oxygenators.
Procedure: Dual hypothermic oxygenated perfusion
Dual hypothermic oxygenated perfusion using the Liver Assist

Device: Liver Assist®
The Liver Assist® is the device used to give the intervention dual hypothermic perfusion.

Procedure: Perfusion fluid
The perfusion fluid is Belzer machine perfusion solution University of Wisconsin (Bridge-to-Life, Ltd., Northbrook, IL).

Drug: Glutathione
Glutathione in a dosage of 3 mmol/ is added to the perfusion fluid according to the intention of use of the perfusion fluid.

No Intervention: Care as usual
The donor liver is procured with a segment of 5 cm circular supratruncal aorta left attached to the coeliac trunc. The patients randomized to the control group will receive a liver graft preserved by conventional SCS without any further intervention.



Primary Outcome Measures :
  1. The incidence of symptomatic non-anastomotic biliary strictures (NAS) [ Time Frame: 6 months ]

    NAS is defined as all of the following criteria:

    • any irregularities or narrowing of the lumen of the intra- or extrahepatic donor bile ducts, but not at the anastomosis
    • which are diagnosed by cholangiogram (preferably by MRCP)
    • in the presence of a patent hepatic artery demonstrated by Doppler ultrasonography and if necessary, by computed tomography angiography
    • and as assessed by the Adjudication Committee
    • when imaging is indicated by clinical signs (i.e., jaundice, cholangitis) or elevation of cholestatic laboratory parameters in blood samples taken during follow-up


Secondary Outcome Measures :
  1. Asymptomatic NAS [ Time Frame: 6 months ]

    Asymptomatic NAS is defined as all of the following:

    • irregularities or narrowing of the lumen of the intra- or extrahepatic donor bile ducts, but not at the anastomosis
    • which are diagnosed by cholangiogram (preferably by MRCP)
    • in the presence of a patent hepatic artery demonstrated by Doppler ultrasonography and if necessary, by computed tomography angiography
    • in the absence of clinical signs (i.e., jaundice, cholangitis) or elevation of cholestatic laboratory parameters in blood samples taken during follow-up

  2. The severity of NAS [ Time Frame: 6 months ]
    Severity and location of NAS is based on assessment of the images of the MRCP obtained in all patients at six months after transplantation (time window of 15 days) which will be performed based on a scoring system described by Buis et. al.

  3. The location of NAS [ Time Frame: 6 months ]
    Assessment of the images of the MRCP obtained in all patients at six months after transplantation (time window of 15 days) which will be performed based on a scoring system described by Buis et. al.

  4. Graft (censored and uncensored for patient death) survival [ Time Frame: 7 days, 1, 3 , 6 months after transplantation ]
  5. Patient survival [ Time Frame: 7 days, 1, 3 , 6 months after transplantation ]
  6. Primary non-function [ Time Frame: 7 days ]
    Defined as liver failure requiring retransplantation or leading to death within seven days after transplantation without any identifiable cause such as surgical problems, hepatic artery thrombosis, portal vein thrombosis and acute rejection

  7. Initial poor function [ Time Frame: 7 days ]
    Defined as a modification of the Olthoff criteria: Prothrombin time/ international normalized ratio (INR) >1.6 and or serum total bilirubin >10 mg/dL on postoperative day 7

  8. Blood pressure [ Time Frame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion ]
    mm Hg

  9. Heart rate [ Time Frame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion ]
    beats per minute

  10. Vasopressor dosage [ Time Frame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion ]
    microgram/kg/min

  11. Length of stay [ Time Frame: 6 months ]
    Length of initial ICU and initial hospital stay is determined in days of admission following liver transplantation. Duration of follow-up hospital stay is determined in days of hospital admission after discharge and up to six months after liver transplantation

  12. Postoperative complications [ Time Frame: 6 months ]
    According to the comprehensive complication index (CCI)

  13. Renal function [ Time Frame: day 7, and 1, 3, 6 months ]
    Estimated glomerular filtration rate (eGFR) according to the 4-variable Modification of Diet in Renal Disease (MDRD) equation

  14. Flow [ Time Frame: At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion ]
    ml/min

  15. Pressure [ Time Frame: At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion ]
    mm Hg

  16. Resistance [ Time Frame: At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion ]
    ml/min/mm Hg

  17. (In selected centers) value of perfusate's pH [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
  18. (In selected centers) value of perfusate's sodium [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    mmol/L

  19. (In selected centers) value of perfusate's potassium [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    mmol/L

  20. (In selected centers) value of perfusate's bicarbonate [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    mmol/l

  21. (In selected centers) value of perfusate's lactate [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    mmol/l

  22. (In selected centers) value of perfusate's alanine transaminase (ALT) [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    U/L

  23. (In selected centers) value of perfusate's aspartate transaminase (AST) [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    U/L

  24. (In selected centers) value of perfusate's alkaline phosphatase (AlkP) [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    U/L

  25. (In selected centers) value of perfusate's gamma glutamyltransferase (γGT) [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    U/L

  26. (In selected centers) value of perfusate's urea [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    mmol/L

  27. (In selected centers) value of perfusate's total bilirubin [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    umol/l

  28. (In selected centers) value of perfusate's thrombomodulin [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    pg/dl

  29. (In selected centers) value of perfusate's high mobility group box-1 (HMBG) protein [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    μg/mL

  30. (In selected centers) value of perfusate's cytochrome C [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
  31. (In selected centers) level of miRNA CDmiR-30e in perfusate [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    relative levels compared to perfusate

  32. (In selected centers) level of miRNA CDmiR-222 in perfusate [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    relative levels compared to perfusate

  33. (In selected centers) level of miRNA CDmiR-296 in perfusate [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    relative levels compared to perfusate

  34. (In selected centers) level of miRNA HDmiR-122 in perfusate [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    relative levels compared to perfusate

  35. (In selected centers) level of miRNA HDmiR-148a in perfusate [ Time Frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion ]
    relative levels compared to perfusate

  36. Histopathological status liver and bile ducts (in selected centers) [ Time Frame: Within 0 to 30 minutes before perfusion, at 2 hours of perfusion, and at 1 hour after reperfusion ]
  37. New onset diabetes after transplantation [ Time Frame: 90 days ]
    • Symptoms of diabetes and random plasma glucose ≥11.1 mmol/L. Symptoms include polyuria, polydipsia, and unexplained weight loss. OR
    • Fasting plasma glucose ≥7.0 mmol/L. Fasting is defined as no caloric intake for at least eight hours. OR
    • Two-hour plasma glucose ≥11.1 mmol/L during an oral glucose tolerance test. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.

  38. Costs of treatment (in selected centers) [ Time Frame: within 6 months after transplantation, including transplant operation ]
    according to the Cost and Outcome analysis of Liver Transplantation (COLT) study

  39. Health related quality of life [ Time Frame: within 6 months before transplantation and 6 months after transplantation ]
    EQ6D questionnaire



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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients (≥ 18 years old)
  • Signed informed consent
  • Willing and able to attend follow-up examinations
  • Donor liver graft from a controlled donation after circulatory death (Maastricht category III)
  • Donors with a body weight ≥40 kg

Exclusion Criteria:

  • Simultaneous participation in another clinical trial that might possibly influence this trial
  • Mental conditions rendering the subject incapable to understand the nature, scope and consequences of the trial
  • Listed for liver transplantation due to fulminant liver failure or retransplantation because of primary non-function
  • Recipient positive test for HIV
  • Donor positive for HIV, Hepatitis B or C
  • Simultaneous transplantation of another organ
  • Patients with contra-indications for MRCP (i.e. pacemaker)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02584283


Contacts
Contact: Robert J. Porte, MD PhD Prof 0031503619027 r.j.porte@umcg.nl
Contact: Rianne van Rijn, MD 0031652724616 r.van.rijn@umcg.nl

Locations
Belgium
Ghent University Hospital Not yet recruiting
Gent, De Pintelaan 185, Belgium, 9000
Contact: Roberto I Troisi, MD, PhD    +3293325519    roberto.troisi@ugent.be   
University Hospitals Leuven Recruiting
Leuven, Herestraat 49, Belgium, 3000
Contact: Diethard Monbaliu, MD, PhD    +3216348727    diethard.monbaliu@uzleuven.be   
Netherlands
Leiden Universtiy Medical Center Not yet recruiting
Leiden, Zuid-Holland, Netherlands, 2333 ZA
Contact: Bart van Hoek, MD, PhD    +31715299756    b.van_hoek@lumc.nl   
University Medical Center Groningen Recruiting
Groningen, Netherlands, 9700 RB
Contact: Rianne van Rijn, MD    +31652724616    r.van.rijn@umcg.nl   
Contact: Robert J Porte, MD, PhD    +31503619027    r.j.porte@umcg.nl   
Erasmus Medical Center Recruiting
Rotterdam, Netherlands, 3015 CE
Contact: Jeroen de Jonge, MD, PhD    +31633330449    j.dejonge.1@umcg.nl   
Sponsors and Collaborators
Robert J. Porte
Erasmus Medical Center
Leiden University Medical Center
Investigators
Principal Investigator: Robert J. Porte, MD PhD Prof University Medical Center Groningen

Additional Information:
Responsible Party: Robert J. Porte, Prof. dr., University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT02584283     History of Changes
Other Study ID Numbers: DHOPE-DCD Trial
First Posted: October 22, 2015    Key Record Dates
Last Update Posted: October 17, 2018
Last Verified: October 2018

Keywords provided by Robert J. Porte, University Medical Center Groningen:
Liver Transplantation
Donation after Circulatory Death
Machine Perfusion

Additional relevant MeSH terms:
Liver Diseases
Liver Failure
End Stage Liver Disease
Hypothermia
Biliary Tract Diseases
Digestive System Diseases
Hepatic Insufficiency
Body Temperature Changes
Signs and Symptoms
Liver Extracts
Hematinics